Brain Metastases
Conditions
Keywords
Whole Brain Radiation, Simultaneous Integrated Boost
Brief summary
This trial is a pilot, Phase 2, sequential two-cohort study designed to test two de-escalated whole brain radiation therapy (WBRT) dose levels and assess their ability to maintain acceptable in-brain distant control. The WBRT dose would decrease as the study moves forward, both in terms of absolute value and equivalent dose in 2 Gray fractions (EQD2) (as determined by the linear quadratic radiobiological model). The absolute value of the simultaneous integrated boost (SIB) dose will change with each dose level because the number of fractions delivered will depend on the WBRT dose. As such, the SIB dose will be manipulated such that the EQD2 will remain essentially equivalent despite the difference in the number of fractions delivered. This design will ensure that the only variable is the change in WBRT dose. The concept is that WBRT with SIB would be expected to maximize both local and in-brain distant control as has already been shown in studies exploring WBRT with SRS boost. However, by itself WBRT with SIB does not address the concern over neurocognitive outcomes. Therefore, investigators hypothesize that there is a lower WBRT dose threshold that will maintain acceptable in-brain distant control, particularly in the setting of a SIB to gross lesions to maintain treated lesion control. In addition, lower overall brain dose (including lower hippocampal dose without specific hippocampal avoidance) may potentially improve neurocognitive function. Investigators are also interested in evaluating treated lesion control, overall survival, neurocognitive sequelae of therapy, quality of life, performance status, and adverse effects of therapy. Biomarker identification for potential correlative circulating tumor DNA and microRNA is an exploratory endpoint to generate data for future prospective evaluation.
Detailed description
Primary Objective Evaluate two de-escalated whole brain radiation dose levels (in the setting of simultaneous integrated boost to gross lesions) with respect to in-brain distant control for brain metastases, defined as an in-brain failure rate outside of the planning target volume at 6 months of \< 20%. Secondary Objectives 1. Evaluate treated lesion control at 6 months for brain metastases in the setting of a predetermined total biologically effective SIB dose as determined by radiographic progression within the planning target volume with fusion and overlay of follow-up MRIs. 2. Evaluate overall survival at 6 months for brain metastases in the setting of WBRT with SIB. 3. Evaluate changes in neurocognitive function after WBRT with SIB in the following domains: verbal learning and memory as assessed by the Hopkins Verbal Learning Test - Revised (HVLT-R). 4. Evaluate changes in health-related quality of life as assessed by the Functional Assessment of Cancer Therapy with Brain Subscale (FACT-Br) after WBRT-SIB for brain metastases. 5. Evaluate changes in performance status as assessed by the Karnofsky Performance Status tool after WBRT-SIB for brain metastases. 6. Evaluate adverse events after WBRT-SIB for brain metastases according to current CTCAE criteria.
Interventions
Sponsors
Indiana University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 18 at time of consent. 2. Ability to provide written informed consent and HIPAA authorization. 3. Pathological diagnosis of any solid tumor histology (from any site in the body). 4. Pathological or clinical (i.e., by imaging) diagnosis of brain metastatic tumor lesions. 5. Total volume of lesions ≤ 30 cm3. 6. Maximum volume of largest lesion ≤ 5 cm3. a. This volume limit would be equivalent to a largest diameter of about 2.1 cm, assuming a perfect sphere. 7. Not a candidate for or eligible for but refused Gamma Knife radiosurgery.
Exclusion criteria
1. Previous radiation to the brain, including WBRT or brain radiosurgery. 2. Life expectancy \< 6 months (as estimated per current ds-GPA). 3. For histologies not included in the ds-GPA publications or otherwise noted online at brainmetgpa.com, the PI will use either published or validated data, or the PI's best clinical judgment to determine the patient's expected survival. 4. Inability to comply with treatment per investigator discretion. 5. Inability to complete neurocognitive assessments per investigator discretion. Of note, tumor lesion number is not an inclusion or
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| In-Brain Distant Failure Rate | 6 Months | An actuarial 6-month rate of new parenchymal lesions seen outside the planning target volume of any lesion that received SIB on any post-treatment MRI (in all 3 planes). This is the binomial proportion of patients who experienced in-brain distant failure by 6 months and the associated 95% confidence interval. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival for Evaluable Patients | 6 Months | An actuarial 6-month rate of patients still alive regardless of disease status. This details the estimated 6-month survival and associated 95% confidence interval from the Kaplan Meier method. For patients who expired, the time from treatment start to death was calculated. Patients who did not expire were censored at the date last know alive. |
| Change in Neurocognitive Function From Baseline to 6 Months | 6 Months | The change in scores from the neurocognitive test were calculated by subtracting the baseline score from the 6-month score. Positive values indicate an increase from baseline and negative values indicate a decrease. The neurological test scores were assessed with the Hopkins Verbal Learning Test - Revised (HVLT). In the HVLT, 12 nouns are read and the participant is asked to recall in 3 rounds. Total words recalled are summed for the Total Recall score ranging from 0-36 (higher score represents better recall). The delayed recall score is tested 20-25 mins after the initial recall and ranges from 0-12 (higher scores are better). Retention (%) is the percentage of words recalled and ranges from 0-100 (higher values represent better recall). The recognition discrimination score is tested by a series of yes/no responses from the participant identifying 12 words from a list of 24 and subtracts the number of true positives minus the true negatives (higher values are better). |
| Change in Health-Related Quality of Life (QoL) From Baseline to 6 Months | 6 Months | The change in scores of health-related quality of life test from baseline to 6 months calculated by subtracting the baseline score from the 6-month score. Positive values indicate an increase in score from baseline to 6 months while negative values indicate a decrease. The Functional Assessment of Cancer Therapy with Brain Subscale (FACT-Br) asks questions on a scale from 0 to 4 with 0 being not at all and 4 being very much. Responses were reversed, if applicable, and compiled to calculate physical well-being (range: 0-28), social/family well-being (range: 0-28), emotional well-being (range: 0-24), functional well-being (range: 0-28), bone marrow transplant (BMT) (range: 0-40), and brain cancer (range: 0-92) subscale scores. These subscale scores were then summed to obtain the trail outcome index (range: 0-148), bone marrow transplant (FACT-BMT) (range: 0-96), general (FACT-G) (range: 0-108), and FACT-Br (range: 0-200) total scores. The higher the score, the better the QoL. |
| Treated Lesion Local Control | 6 Months | An actuarial 6-month rate of any new, recurrent, or progressing (as defined by Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria) tumor within the planning target volume on any post-treatment MRI. This details the estimated 6-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to local failure was calculated. Patients who did not experience local failure were censored at the date last know alive or at the date of death if they expired. |
| Incidence of Early and Late Treatment-Related Adverse Effects | Up To 39 Months | This is the percentage of eligible patients who experienced the respective treatment-related AE while on study. Adverse effects (AEs) were defined per CTCAE and considered treatment-related if the AE start date occurred on or after the first date of treatment and it was possibly, probably, or definitely related to treatment. AEs were recorded from the start of treatment until the patient was off-study. |
| Overall Survival for Eligible Patients | 6 Months | An actuarial 6-month rate of patients still alive regardless of disease status. This details the estimated 6-month survival and associated 95% confidence interval from the Kaplan Meier method. For patients who expired, the time from treatment start to death was calculated. Patients who did not expire were censored at the date last know alive. |
| Change in Neurocognitive Function Retention Percentage Raw Score From Baseline to 6 Months | 6 Months | The change in scores from the neurocognitive test were calculated by subtracting the baseline score from the 6-month score. Positive values indicate an increase from baseline and negative values indicate a decrease. The neurological test scores were assessed with the Hopkins Verbal Learning Test - Revised (HVLT). In the HVLT, 12 nouns are read and the participant is asked to recall in 3 rounds. Total words recalled are summed for the Total Recall score ranging from 0-36 (higher score represents better recall). The delayed recall score is tested 20-25 mins after the initial recall and ranges from 0-12 (higher scores are better). Retention (%) is the percentage of words recalled and ranges from 0-100 (higher values represent better recall). The recognition discrimination score is tested by a series of yes/no responses from the participant identifying 12 words from a list of 24 and subtracts the number of true positives minus the true negatives (higher values are better). |
| Change in Performance Status | 12 Months | Total change in performance status score was calculated by substracting the baseline score from the follow-up score. Positive values indicate an increase in score from baseline while negative values indicate a decrease in score from baseline. Functional status evaluated using the Karnofsky Performance Score (KPS) Index. The KPS score is evaluated on a scale from 0 to 100 where 0 is death and 100 is normal no complaints; no evidence of disease. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort A Standard PCI dose
Cohort A: Cohort A - WBRT dose = 25 Gy, SIB dose = 42 Gy, # of daily fractions = 10, SIB dose in EQD2 = 49.7 Gy | 20 |
| Cohort B Low PCI dose
Cohort B: Cohort B - WBRT dose = 20 Gy, SIB dose = 40 Gy, # of daily fractions = 8, SIB dose in EQD2 = 50.0 Gy | 0 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
Baseline characteristics
| Characteristic | Cohort A | Total |
|---|---|---|
| Age, Continuous | 59.8 years STANDARD_DEVIATION 15.12 | 59.8 years STANDARD_DEVIATION 15.12 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants |
| Number of Boosted Lesions at Baseline | 7.00 lesions | 7.00 lesions |
| Number of Lesions at Baseline | 7.00 lesions | 7.00 lesions |
| Primary Cancer Diagnosis Bladder | 1 Participants | 1 Participants |
| Primary Cancer Diagnosis Breast | 5 Participants | 5 Participants |
| Primary Cancer Diagnosis Colon | 1 Participants | 1 Participants |
| Primary Cancer Diagnosis Kidney | 1 Participants | 1 Participants |
| Primary Cancer Diagnosis Lung | 11 Participants | 11 Participants |
| Primary Cancer Diagnosis Skin - Scalp and Neck | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 17 Participants | 17 Participants |
| Region of Enrollment United States | 20 participants | 20 participants |
| Sex: Female, Male Female | 11 Participants | 11 Participants |
| Sex: Female, Male Male | 9 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 15 / 20 | 0 / 0 |
| other Total, other adverse events | 20 / 20 | 0 / 0 |
| serious Total, serious adverse events | 9 / 20 | 0 / 0 |
Outcome results
Primary
In-Brain Distant Failure Rate
An actuarial 6-month rate of new parenchymal lesions seen outside the planning target volume of any lesion that received SIB on any post-treatment MRI (in all 3 planes). This is the binomial proportion of patients who experienced in-brain distant failure by 6 months and the associated 95% confidence interval.
Time frame: 6 Months
Population: Includes the patients evaluable for in-brain distant failure at 6 months. There were no patients accrued in cohort B.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A | In-Brain Distant Failure Rate | 0.444 proportion of patients |
Secondary
Change in Health-Related Quality of Life (QoL) From Baseline to 6 Months
The change in scores of health-related quality of life test from baseline to 6 months calculated by subtracting the baseline score from the 6-month score. Positive values indicate an increase in score from baseline to 6 months while negative values indicate a decrease. The Functional Assessment of Cancer Therapy with Brain Subscale (FACT-Br) asks questions on a scale from 0 to 4 with 0 being not at all and 4 being very much. Responses were reversed, if applicable, and compiled to calculate physical well-being (range: 0-28), social/family well-being (range: 0-28), emotional well-being (range: 0-24), functional well-being (range: 0-28), bone marrow transplant (BMT) (range: 0-40), and brain cancer (range: 0-92) subscale scores. These subscale scores were then summed to obtain the trail outcome index (range: 0-148), bone marrow transplant (FACT-BMT) (range: 0-96), general (FACT-G) (range: 0-108), and FACT-Br (range: 0-200) total scores. The higher the score, the better the QoL.
Time frame: 6 Months
Population: Includes patients evaluable for 6-month outcomes. There were no patients accrued in cohort B.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort A | Change in Health-Related Quality of Life (QoL) From Baseline to 6 Months | Physical Well-Being | -1.00 scores on a scale |
| Cohort A | Change in Health-Related Quality of Life (QoL) From Baseline to 6 Months | Social/Family Well-Being | -2.00 scores on a scale |
| Cohort A | Change in Health-Related Quality of Life (QoL) From Baseline to 6 Months | Emotional Well-Being | -1.00 scores on a scale |
| Cohort A | Change in Health-Related Quality of Life (QoL) From Baseline to 6 Months | Functional Well-Being | -1.00 scores on a scale |
| Cohort A | Change in Health-Related Quality of Life (QoL) From Baseline to 6 Months | Bone Marrow Transplant (BMT) Subscale | 0.00 scores on a scale |
| Cohort A | Change in Health-Related Quality of Life (QoL) From Baseline to 6 Months | Trial Outcome Index | -4.00 scores on a scale |
| Cohort A | Change in Health-Related Quality of Life (QoL) From Baseline to 6 Months | FACT-G | -2.00 scores on a scale |
| Cohort A | Change in Health-Related Quality of Life (QoL) From Baseline to 6 Months | FACT-BMT | -1.00 scores on a scale |
Secondary
Change in Neurocognitive Function From Baseline to 6 Months
The change in scores from the neurocognitive test were calculated by subtracting the baseline score from the 6-month score. Positive values indicate an increase from baseline and negative values indicate a decrease. The neurological test scores were assessed with the Hopkins Verbal Learning Test - Revised (HVLT). In the HVLT, 12 nouns are read and the participant is asked to recall in 3 rounds. Total words recalled are summed for the Total Recall score ranging from 0-36 (higher score represents better recall). The delayed recall score is tested 20-25 mins after the initial recall and ranges from 0-12 (higher scores are better). Retention (%) is the percentage of words recalled and ranges from 0-100 (higher values represent better recall). The recognition discrimination score is tested by a series of yes/no responses from the participant identifying 12 words from a list of 24 and subtracts the number of true positives minus the true negatives (higher values are better).
Time frame: 6 Months
Population: Includes patients evaluable for 6-month outcomes. There were no patients accrued in cohort B.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort A | Change in Neurocognitive Function From Baseline to 6 Months | Total Recall Raw Score | -1.00 difference in score on a scale |
| Cohort A | Change in Neurocognitive Function From Baseline to 6 Months | Delayed Recall Raw Score | -1.00 difference in score on a scale |
| Cohort A | Change in Neurocognitive Function From Baseline to 6 Months | Recognition Discrimination Index Raw Score | 0.00 difference in score on a scale |
Secondary
Change in Neurocognitive Function Retention Percentage Raw Score From Baseline to 6 Months
The change in scores from the neurocognitive test were calculated by subtracting the baseline score from the 6-month score. Positive values indicate an increase from baseline and negative values indicate a decrease. The neurological test scores were assessed with the Hopkins Verbal Learning Test - Revised (HVLT). In the HVLT, 12 nouns are read and the participant is asked to recall in 3 rounds. Total words recalled are summed for the Total Recall score ranging from 0-36 (higher score represents better recall). The delayed recall score is tested 20-25 mins after the initial recall and ranges from 0-12 (higher scores are better). Retention (%) is the percentage of words recalled and ranges from 0-100 (higher values represent better recall). The recognition discrimination score is tested by a series of yes/no responses from the participant identifying 12 words from a list of 24 and subtracts the number of true positives minus the true negatives (higher values are better).
Time frame: 6 Months
Population: Includes patients evaluable for 6-month outcomes. There were no patients accrued in cohort B.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A | Change in Neurocognitive Function Retention Percentage Raw Score From Baseline to 6 Months | -3.00 percentage |
Secondary
Change in Performance Status
Total change in performance status score was calculated by substracting the baseline score from the follow-up score. Positive values indicate an increase in score from baseline while negative values indicate a decrease in score from baseline. Functional status evaluated using the Karnofsky Performance Score (KPS) Index. The KPS score is evaluated on a scale from 0 to 100 where 0 is death and 100 is normal no complaints; no evidence of disease.
Time frame: 12 Months
Population: Includes patients evaluable for 6-month outcomes. There were no patients accrued in cohort B.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort A | Change in Performance Status | Baseline to 3 Months | -10.00 difference in score on a scale |
| Cohort A | Change in Performance Status | Baseline to 6 Months | 0.00 difference in score on a scale |
| Cohort A | Change in Performance Status | Baseline to 12 Months | 0.00 difference in score on a scale |
Secondary
Incidence of Early and Late Treatment-Related Adverse Effects
This is the percentage of eligible patients who experienced the respective treatment-related AE while on study. Adverse effects (AEs) were defined per CTCAE and considered treatment-related if the AE start date occurred on or after the first date of treatment and it was possibly, probably, or definitely related to treatment. AEs were recorded from the start of treatment until the patient was off-study.
Time frame: Up To 39 Months
Population: Includes the patients marked as eligible who started treatment. There were no patients accrued in cohort B.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort A | Incidence of Early and Late Treatment-Related Adverse Effects | Fatigue | 50.00 percentage of patients |
| Cohort A | Incidence of Early and Late Treatment-Related Adverse Effects | Alopecia | 30.00 percentage of patients |
| Cohort A | Incidence of Early and Late Treatment-Related Adverse Effects | Memory Impairment | 25.00 percentage of patients |
| Cohort A | Incidence of Early and Late Treatment-Related Adverse Effects | Headache | 10.00 percentage of patients |
| Cohort A | Incidence of Early and Late Treatment-Related Adverse Effects | Somnolence | 10.00 percentage of patients |
| Cohort A | Incidence of Early and Late Treatment-Related Adverse Effects | Blurred Vision | 5.00 percentage of patients |
| Cohort A | Incidence of Early and Late Treatment-Related Adverse Effects | Cognitive Disturbance | 5.00 percentage of patients |
| Cohort A | Incidence of Early and Late Treatment-Related Adverse Effects | Dermatitis Radiation | 5.00 percentage of patients |
| Cohort A | Incidence of Early and Late Treatment-Related Adverse Effects | Dry Skin | 5.00 percentage of patients |
| Cohort A | Incidence of Early and Late Treatment-Related Adverse Effects | Mucosal Infection | 5.00 percentage of patients |
| Cohort A | Incidence of Early and Late Treatment-Related Adverse Effects | Oral Pain | 5.00 percentage of patients |
| Cohort A | Incidence of Early and Late Treatment-Related Adverse Effects | Papulopustular Rash | 5.00 percentage of patients |
| Cohort A | Incidence of Early and Late Treatment-Related Adverse Effects | Pruritus | 5.00 percentage of patients |
| Cohort A | Incidence of Early and Late Treatment-Related Adverse Effects | Rash Maculo-Papular | 5.00 percentage of patients |
| Cohort A | Incidence of Early and Late Treatment-Related Adverse Effects | Skin and Subcutaneous Tissue Disorders | 5.00 percentage of patients |
| Cohort A | Incidence of Early and Late Treatment-Related Adverse Effects | Vomiting | 5.00 percentage of patients |
Secondary
Overall Survival for Eligible Patients
An actuarial 6-month rate of patients still alive regardless of disease status. This details the estimated 6-month survival and associated 95% confidence interval from the Kaplan Meier method. For patients who expired, the time from treatment start to death was calculated. Patients who did not expire were censored at the date last know alive.
Time frame: 6 Months
Population: Includes patients who started treatment and were deemed eligible for the study. There were no patients accrued in cohort B.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A | Overall Survival for Eligible Patients | 0.700 survival probability |
Secondary
Overall Survival for Evaluable Patients
An actuarial 6-month rate of patients still alive regardless of disease status. This details the estimated 6-month survival and associated 95% confidence interval from the Kaplan Meier method. For patients who expired, the time from treatment start to death was calculated. Patients who did not expire were censored at the date last know alive.
Time frame: 6 Months
Population: Includes patients evaluable for 6-month outcomes. There were no patients accrued in cohort B.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A | Overall Survival for Evaluable Patients | 1.000 survival probability |
Secondary
Treated Lesion Local Control
An actuarial 6-month rate of any new, recurrent, or progressing (as defined by Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria) tumor within the planning target volume on any post-treatment MRI. This details the estimated 6-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to local failure was calculated. Patients who did not experience local failure were censored at the date last know alive or at the date of death if they expired.
Time frame: 6 Months
Population: Includes patients evaluable for 6-month outcomes. There were no patients accrued in cohort B.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A | Treated Lesion Local Control | 1.000 survival probability |